Propoxyphene salts

ABSTRACT

The Alpha -d and Alpha -l forms of the 4-chloro-m-toluenesulfonate and 3,4-dichlorobenzenesulfonate salts of propoxyphene. These salts are suitable for formulation of these analgesic and antitussive compounds into aqueous suspensions having acceptable taste characteristics.

United States Patent 1191 Stephens v 1 Apr. 17, 1973 1541 PROPOXYPHENE-SALTS [56] References Cited [75 Inventor: Verlin C. Stephens,Indianapolis, UNITED STATES PATENTS V 4 v 2,728,779 12/1955 Pohland..260/49O 3,065,261 11/1962 Stephens ..260/490 [.73] Asslgnee' gr andCompany Indlanapohs 3,395,146 7/1968 Satzinger ..260/490 [22] Filed;June 29, 1971 Primary Examiner-Vivian Garner Atl0rneyEveret F. Smith eta1. 21 Appl. No; 158,126

' 57] ABSTRACT [52] US. Cl. ..260/490, 260/326.3, 424/274, The a-d anda-l forms of the 4 chloro-fn-tal ane-sul- 424/31 1 fonate and 3,4-dichlorobenzenesulfonate salts of [51] Int. CL... ..C07c-143/84pr0p0Xyphene. These salts are suitable for formulation Field of Search..260/49O Of these analgesic and amimssive compounds imo aqueoussuspensions having acceptable tastecharacteristics. I

7 Claims, N0 Drawings PROPOXYPHENE SALTS BACKGROUND OF THE INVENTION 1.Field of the Invention This invention relates to the4-chloro-m-toluenesulfonate and the 3,4-dichlorobenzenesulfonate saltsof the a-dand a-l forms of propoxyphene (1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane). The a-d-isomer hereinafteris referred to as d-propoxyphene and the a-l-isomer as l-propoxyphene.The dpropoxyphene and l-propoxyphene salts of this invention areimproved compounds useful as analgesics and antitussive s, respectively.

2. Description of the Prior Art Propoxyphene possesses two centers ofasymmetry and therefore occurs in diastereoisomeric forms. The lesssoluble diastereoisomers are designated as the alpha isomers and themore soluble as the beta isomers. The present invention is concernedonly with the alpha isomers, since it has been found that the betaisomers have little or no pharmaceutical activity. U.S. Pat. No.2,728,779 discloses the preparation of the a-d,l-racemate as the freebase and as certain acid addition salts thereof. The a-d,l-racemicmixture, although pharmacologically active, is resolved into the a-lcompound which is an excellent antitussive and the a-d compound 1 whichis an analgesic of outstanding usefulness, having little or no tendencyto produce addiction.

- The base compounds have a characteristic, intensely bitter flavorwhich gives rise to problems in preparing formulations for use by oraladministration. The flavor is a particularly severe problem in preparingformulations of the compounds for use in the form of suspensions.Because of their bitter taste, it is not practical to formulate thepropoxyphene materials of U.S. Pat. No. 2,728,779 into pediatricsuspensions.

U.S. Pat. No. 3,065,261 discloses the 2- naphthalenesulfonate salts ofdand l-propoxyphene as compounds having improved taste, good stabilityand very low solubility in water. These salts possess essentially thesame pharmaceutical activity as the free base and the same substantialfreedom from side effects.

Thepresent invention involves the discovery of two new salts of dandl-propoxyphene. These salts avoid the problem of the highly unpleasanttaste of the parent compound while retaining the desired pharmacologicalactivity. Furthermore, these compounds are significantly less solublethan the Z-naphthalene sulphonate salts described in U.S. Pat. No.3,065,261. The salts of this invention, because of their markedlydecreased taste intensity, can be prepared in the form of pediatricsuspensions of excellent acceptability SUMMARY OF THE INVENTION Thepropoxyphene base employed in preparing the compositions of thisinvention has the following formula:

The d and l-propoxyphene 4-chloro-m-toluenesulfonate and3,4-dichlorobenzenesulfonate salts are only slightly soluble in water,0.72 mg/ml (at 33C.) for the a-dand a-l-4-chloro-m-toluenesulfonate and0.38

mg/ml (at 25C.) for the a-d and a-l-3,4- dichlorobenzenesulfonate. Therates of solution are very slow, 0.075 mg/ml after 1 hour for the d andlpropoxyphene -propoxyphene 4-chloro-m-toluenesulfonate salts, and 0.2mg/ml after one hour for the 3,4- dichlorobenzenesulfonates. Suchsolubility characteristics provide a highly desirable sustained releaseof the analgesic and I antitussive effect of these compounds, The saltsof this invention also have a pleasant flavor of excellent acceptabilitywhen formulated into suspensions for oral administration. These tasteproperties are in marked contrast to the bitter taste of the free .baseand hydrochloride salts of a-d and al-propoxyphene. Also, the salts ofthis invention have formulating characteristics which facilitate theircombination into an oral dosage form with aspirin, having excellenttaste properties and greater stability than the hydrochloride or2-naphthalenesulfonate.

DETAILED DESCRIPTION OF THE INVENTION The novel salts of this inventionare readily prepared by reacting the propoxyphene base compound as thehydrohalide or other strong acid salt at elevated temperatures in aninert mutual solvent with a salt of 4- chloro-m-toluenesulfonic acid or3 ,4-

dichlorobenzenesulfonic acid, followed by cooling of the reactionmixture to crystallize the desired propoxyphene alt. The sodium,potassium, calcium, or other soluble alkali metal or alkaline earthmetal saltof the acid can suitably be employed. The' solvent can beaqueous ethanol, methanol or other. inert mutual solvent. Preferably thesolvent is an aquous solution of a water-miscible alcohol containingfrom about 25 to 50 percent by volume of the alcohol. Sincethesolubility characteristics of the reactants are well known othersolvents can be ascertained readily. The desired solid reaction productcan be separated from the liquid phase, leaving the by-product saltresulting from the reaction (e.g. sodium chloride) behind in the liquidphase when an aqueous solvent is utilized. After separation, the solidreaction product is washed with water to remove any occluded 'by-productsalt, and then is re-crystallized, if desired, from aqueous alcohol.Other techniques can be employed in preparing the novel salts of thisinvention, for example, by dissolving the base compound and a slightmolar excess of the 4- chloro-m -toluenesulfonic acid or 3 ,4-dichlorobenzenesulfonic acid in an inert mutual solvent at elevatedtemperatures and .thereafter filtering to remove any undissolvedmaterial, followed by cooling, whereupon the desired salts of the basecompound crystallize in good yield. Separation of the salts of the basecompound can be by filtration or the like.

In a further alternative procedure, the base compound in the form of astrong acid salt can be reacted in aqueous solution with the 4-chlorom-toluenesulfonic acid or 3,4-dichlorobenzene-sulfonic acid itself, and

the desired corresponding salt of the base compoundprecipitatedtherefrom.

The product compounds of the present invention are readily prepared inan aqueous suspension suitable for pediatric and general use byhomogenizing with an aqueous vehicle of conventional type containing asuspending agent, a sweetening agent, and a flavoring material.

' a pharmaceutically acceptable 4-chloro-m-toluenesulfonate salt or3,4-dichlorobenzene-sulfonate salt, e.g.a

- sodium or other alkali metal or alkaline earth metal sulfonate, tominimize the taste of the medicament. Taste improvement is observed evenwith very low proportions of such added salts, and the effect isincreased at proportions up to the saturation level. It is generallypreferred to add the salt in a proportion between about one andaboutthree percent by weight of the total suspension.

in the preparation of the new dbmpounds and of the suspensions thereof,it is of course important to employ a grade of4-chloro-m-toluenesulfonic acid and 3,4- dichlorobenzenesulfonic acid orits salts having essentially no pharmaceuticallyobjectionableimpurities,

and particularly having no impurities with objectionable tasteproperties.

The preparation of the'racemic propoxyphene and resolution thereof intoits dextro and levo forms are well known, for example see U.S.' Pat.Nos. 2,728,779

and 3,065,261,8nd J. Am. Chem. 806., 77, 3400 (1955) and]. Am. Chem.Sim, '75, 4458 (1953).

Thefbase compounds set forth in these patents are repre-sented by thefollowing formula:

'3,4-dichlorobenzenesulfonate salts of the compounds represented by (11)therefore form an embodiment of this invention.

' The following examples more specifically illustrate this invention.

EXAMPLE 1 Purified sodium 4-chloro-m-toluenesulfonate (2.28 gm, 0.01mole) is dissolved in cc of water. To cc of water is addedl-propoxyphene hydrochloride (3.75 gm., 0.01 mole) with heating untilall solids are dissolved. These solutions are then combined and form aheavy crystalline precipitate, which dissolves upon the addition of 50cc methanol and heating. This solution is filtered hot to remove anyundissolved material. The filtrate is diluted with distilled water toabout 200 cc and allowed to stand. Large shiny platelets separate bycrystallization and are filtered off; weight 4.7 gm. The productobtained in this way assays 57.2% propoxyphene base, 3.16% H 0, and hasa solubility in water of 0.72 mg/ml at 33C. The rate of solution is veryslow, only about 0.075 mg/ml at 1 hour.

EXAMPLE 2 a-d-Propoxyphene hydrochloride is converted into the4-chloro-m-toluenesulfonate salt derivative according to the procedureof Example l. The product is a white crystallne material having the samemelting point and solubility as the a-l isomer.

The following example shows that the sulfonate salt need not bepurified. in this example sodium 4-chlorom-toluenesulfonate tailings areemployed in the preparation of the d-propoxyphene salt.

EXAMPLE 3 Sodium 4-chloro-m-toluenesulfonate (114 gm.) in 500 cc wateris boiled, filtered, cooled and recrystallized. The recrystallizedmaterial contains the purified sodium salt. The filtrate containsimpure, sodium 4- chloro-m-toluenesulfonate. To this filtrate is added15 gm. of d-propoxyphene hydrochloride in 200 cc ethanol. Theprecipitate immediately formed is collected and washed with water, anddried in a vacuum oven. d-Propoxyphene 4-chloro-m-toluenesulfonate (20gm) having a melting point of l26-l32C. is obtained. This product isrecrystallized from an ethanolwater mixture (ethanol l00 cc, water cc)and cooled over-night. The solids thus formed are filtered and washedwith water followed by drying in air, using a heat lamp, to obtain 17.8gm. of the 4-chloro-mtoluenesulfonate salt of d-propoxyphene having amelting point of l25-l 33C. and a solubility of 0.72 mg/ml in water at33C. The product assays 59.1% propoxyphene base, 3.11% H O. The taste ofthis product is not significantly different from that obtained usingpurified sodium 4-chloro-m-toluenesulfonate.

EXAMPLE 4 ing at l20-l30C. and having a solubility of 0.38

mg/ml (at 25C.). Assay 57.9% propoxyphene, 3.3% water.

EXAMPLE 5 a-l-Propoxyphene 3,4-dichlorobenzenesulfonate is prepared froma-l-propoxyphene hydrochloride, as in Example 4. The product is a shinywhite crystalline material having the same melting point and solubilityas the a-d-isomer.

The hydrochloride salts of the base compound of formula 11 above can beconverted into the corresponding sulfonate salts by reacting 1 mole ofsodium 4-chlorom-toluenesulfonate or 1 mole of the selected basecompound according to the procedure of Example 1 to produce thefollowing new compounds:

a-l-l ,2-diphenyl-2-propionoxy-3-methyl-4- dimethylaminobutane4-chloro-m-toluenesulfonate,

a-d-l ,2-diphenyl-Z-propionoxy-3-methyl-4- dimethylaminobutane4-chloro-m-toluenesulfonate,

a-l-l ,2-diphenyl-2-acetoxy-3-methyl-4- dimethylaminobutane4-chloro-m-toluenesulfonate,

a d -l ,2-diphenyl-2-propionoxy-3-methyl-4-pyrrolidinobutane4-chloro-m-toluenesulfonate,

a-ll ,2-diphenyl-2-propionoxy-3-methyl-4- dimethylaminobutane3,4-dichlorobenzenesulfonate,

a-d-l ,Z-diphenyl-2-propionoxy-3-methyl 4- dimethylaminobutane 3,4-dichlorobenzenesulfonate,

a-l-l ,2-diphenyl-2-acetoxy-3methyl-4- dimethylaminobutane3,4-dichlorobenzenesulfonate,

EXAMPLE 6 An analgesic aqueous suspension containing 20 mg/ml ofa-d-propoxyphene 4-chloro-m-toluenesul fonate is prepared according tothe following procedre.

The suspension has the following composition:

Par t1 Sodium 4-chloro-m-toluenesulfonic acid 200 g. Citric acid 4.25 g.Saccharin, soluble 5.0 g. Water, distilled 450 ml.

Part II vMethyl cellulose, I500 cp. at 2% 5.0 g. Methyl cellulose, 4000cp. at 2% L g.

Part III Sucrose 600.0 g.

Part IV Glucose I00 g.

Part V and-propoxyphene 4-chloro-m-toluenesulfonate 20.3 g.

Part VI Silicone emulsion, 30 percent 3.3 g. Water, distilled ml PartVII F.D. and c. Red No.2 0.05 g. F.D. and C. Yellow No. 6 0.01 g. Water,distilled 10 ml.

Part VIII Cherry flavor, imitation 2.0 ml Cherry pit flavor, imitation0.5 ml

Part IX Ethanol, 95 percent 10.5 ml. Methyl parahydroxybenzoate 0.3 g.Propyl parahydroxybenzoate 0.15 g. Butyl parahydroxybenzoate 0.15 g. Oilof peppermint 0.01 ml.

Part X Water, distilled q.s. to 1000.0 ml.

Part I is mixed, dissolved, and heated to 90C. Part II is added andmixed well with the solution, and the mixture is stirred while coolingto 30C. to effect complete solution. Parts III and IV are successivelyadded and dissolved. Part V is added in the form of a finely dividedpowder and mixed well for 10 'minutes. Parts VI,

VII, VIII, and IX are successivelyadded and mixedv well, after whichdistilled water (Part X) is added in a quantity sufficient to adjust thevolume to 1,000 ml.

The final mixture is homogenized.

The complete product has a pleasant cherry flavor of excellentacceptability in taste-panel tests.

EXAMPLE7 An antitussive aqueous suspension containing 17.5 mg/ml ofa-l-propoxyphene 4-chloro-m-toluenesulfonate is prepared using .theproportions and procedures of Example 6 with the following modifications:

Part V al-propoxyphene 4-chloro-m4oluenesulfonate 17.5 g.

Part VII PD. and C. Yellow No. 5 0.1 g. Water, distilled 10 ml.

Parts VII and IX Ethanol, 95 percent 10.5 ml. Methyl parahydroxybenzoate0.3 g. Propyl parahydroxybenzoate 0. l 5 g. Butyl parahydroxybenzoate0.15 g. Lcmonlime flavor, imitation 0.3 ml.

The completed suspension has a pleasant citrus flavor of excellentacceptability in taste-panel tests.

The toxicity of the a-d and 04-1 propoxyphene 4-chloro-m-toluenesulfonate and 3,4- dichlorobenzenesulfonate salts ofthis invention is determined byorally dosing fasted mice. After 7 daysobservation, the LD (dose at which half the mice tested died) of thesenovel salts, in each case, is greater than 1,000 mg/kg. Determined bythe same method, the toxicity of d-propoxyphene 2-naphthalenesulfonatelfonate is LD =765il 26 mg/kg.

I claim:

1. The 4-chloro-m-toluenesulfonate or 3,4- dichloroben zenesulfonatesalts of the a-d and a-l forms of a base represented by the formula 2.The 4-chloro-m-toluenesulfonate salts of the'a-d' 4..The4-chloro-m-toluenesulfonate salt of the 01-1 7 form of the base of claim1.

5. The 3,4-dichlorobenzenesulfonate salts of the a-d and a-l forms ofthe base of claim 1.

6. The 3,4-dichlorobehzenesulfonate saltof the a-d form ofthe'base ofclaim 1. j

7. The 3,4-dichlorobenzenesulfonate salt of the 01-] form of the base ofclaim I.

2. The 4-chloro-m-toluenesulfonate salts of the Alpha -d and Alpha -lforms of the base of claim
 1. 3. The 4-chloro-m-toluenesulfonate salt ofthe Alpha -d form of the base of claim
 1. 4. The4-chloro-m-toluenesulfonate salt of the Alpha -l form of the base ofclaim
 1. 5. The 3,4-dichlorobenzenesulfonate salts of the Alpha -d andAlpha -l forms of the base of claim
 1. 6. The3,4-dichlorobenzenesulfonate salt of the Alpha -d form of the base ofclaim
 1. 7. The 3,4-dichlorobenzenesulfonate salt of the Alpha -l formof the base of claim 1.